Piperidine derivatives and process for their production

ABSTRACT

The present invention relates to substantially pure piperidine derivative compounds of the formulae: 
     
       
         
         
             
             
         
       
         
         
           
             wherein
           R 1  is hydrogen or hydroxy;   R 2  is hydrogen;   
         
             or R 1  and R 2  taken together form a second bond between the carbon atoms bearing R 1  and R 2 ;
           R 3  is —COOH or —COOR 4 ;   R 4  has 1 to 6 carbon atoms;   A, B, and D are the substituents of their respective rings, each of which may be different or the same and are hydrogen, halogens, alkyl, hydroxy, alkoxy, or other substituents.   
         
           
         
       
    
     A process of preparing such piperidine derivative compounds in substantially pure form is also disclosed.

FIELD OF THE INVENTION

The present invention relates to piperidine derivatives and a processfor their production.

BACKGROUND OF THE INVENTION

Terfenadine,1-(p-tert-butylphenyl)-4-[4′-(α-hydroxydiphethylmethyl)-1′-piperidinyl]-butanolis a non-sedating anti-histamine. It is reported to be a specificH₂-receptor antagonist that is also devoid of any anticholingeric,anti-serotoninergic, and anti-adrenergic effects both in vitro and invivo. See D. McTavish, K. L. Goa, M. Ferrill, Drugs, 1990, 39, 552; C.R. Kingsolving, N. L. Monroe, A. A. Carr, Pharmacologist, 1973, 15, 221;J. K. Woodward, N. L. Munro, Arzneim-Forsch, 1982, 32, 1154; K. V. Mann,K. J. Tietze, Clin. Pharm. 1989, 6, 331. A great deal of effort has beenmade investigating structure-activity relationships of terfenadineanalogs, and this is reflected in the large number of U.S. patentsdisclosing this compound and related structures as follows:

U.S. Pat. No. 3,687,956 to Zivkovic

U.S. Pat. No. 3,806,526 to Carr, et. al.

U.S. Pat. No. 3,829,433 to Carr, et. al.

U.S. Pat. No. 3,862,173 to Carr, et. al.

U.S. Pat. No. 3,878,217 to Carr, et. al.

U.S. Pat. No. 3,922,276 to Duncan, et. al.

U.S. Pat. No. 3,931,197 to Carr, et. al.

U.S. Pat. No. 3,941,795 to Carr, et. al.

U.S. Pat. No. 3,946,022 to Carr, et. al.

U.S. Pat. No. 3,956,296 to Duncan, et. al.

U.S. Pat. No. 3,965,257 to Carr, et. al.

U.S. Pat. No. 4,742,175 to Fawcett, et. al.

Terfenadine has been linked to potentially fatal abnormal heart rhythmsin some patients with liver disease or who also take the antifungal drugketoconazole or the antibiotic erythromycin. In animal and humanmetabolic studies, terfenadine was shown to undergo high first-passeffect, which results in readily measurable plasma concentrations of themajor metabolite4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylaceticacid, also known as terfenadine carboxylic acid metabolite. Theterfenadine carboxylic acid metabolite also possesses anti-histaminicactivity in animal models and may lack the cardiac side effects seenwith terfenadine.

Piperidine derivatives related to the terfenadine carboxylic acidmetabolite are disclosed in the following U.S. patents:

U.S. Pat. No. 4,254,129 to Carr, et. al.

U.S. Pat. No. 4,254,130 to Carr, et. al.

U.S. Pat. No. 4,285,957 to Carr, et. al.

U.S. Pat. No. 4,285,958 to Carr, et. al.

In these patents,4-[4-[(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneaceticacid and related compounds are prepared by alkylation of a substitutedpiperidine derivative of the formula:

with an ω-haloalkyl substituted phenyl ketone of the formula:

wherein the substituents halo, R₁, R₂, n, z, and R₆ are described incolumn 6 of U.S. Pat. No. 4,254,130.

It is further described that the ω-haloalkyl substituted phenyl ketonewherein Z is hydrogen are prepared by reacting an appropriate straightor branched lower alkyl C₁₋₆ ester of α,α-dimethylphenylacetic acid withthe compound of the following formula:

under the general conditions of a Friedel-Crafts acylation, wherein haloand m are described in column 11 of U.S. Pat. No. 4,254,129. Thereaction is carried out in carbon disulfide as the preferred solvent.

Applicant has discovered that the preparation of ethyl4-(4-chloro-1-oxobutyl)-α,αdimethylphenylacetate by reaction of4-chlorobutyryl chloride, aluminum chloride, and ethylα,α-dimethylphenylacetate in carbon disulfide, as described in Example 1of U.S. Pat. Nos. 4,254,130 and 4,285,958 provides an inseparablemixture of monosubstituted aromatic regioisomers of the formula:

wherein the chlorobutyryl substituent is attached at either of the threearomatic carbons which are meta or para to the dimethylacetatesubstituent. These regioisomers are not separable by standard techniquesof thin layer chromatography, or column chromatography, and low field:proton nuclear magnetic resonance spectroscopy is inconclusive inidentifying the product of this reaction as a mixture. When the mixtureof monosubstituted aromatic regioisomers of the preceding formula isreacted with a piperidine of the formula:

a second mixture of aromatic regioisomers is obtained of the formula:

wherein the monosubstituted meta, para mixture of regioisomers isobtained.

It is known in the art that a monoalkyl substituent on a benzene ring isortho, para directing in electrophilic aromatic substitution reactionssuch as a Friedel-rafts reaction. Thus, it would be expected that theFriedel-Crafts reaction of α-chlorobutyryl chloride with ethylα,α-dimethylphenylacetate would yield predominantly the para substitutedproduct of the formula:

because of the electron donating, para-directing character of thedimethylalkyl substituent combined with the steric hindrance associatedwith reaction of the ortho positions. In practice, the inductiveelectronic withdrawing effect of the carboxylic ester of ethylα,α-dimethylphenylacetate counteracts the expected alkyl electrondonating effect, resulting in no significant directing effect for thearomatic substitution reaction. For the described reaction, astatistical mixture of meta to para regioisomers results, with the twometa positions predominating.

The above second mixture of regioisomers can be converted to a thirdmixture of regioisomers of formula:

Although the second mixture of regioisomers and the third mixture ofregioisomers can be analyzed by HPLC experiments, a practical separationto obtain gram quantities of substantially pure regioisomers has notbeen achieved. Each mixture (including the first), would be expected tocontain 33% of the para isomer and 67% of the meta isomer. Since thesecomponents are inseparable, it has not been possible to obtain either ofthe regioisomers in each mixture in substantially pure form.

SUMMARY OF THE INVENTION

The present invention relates to substantially pure piperidinederivative compounds of the formulae:

-   -   wherein        -   R₁ is hydrogen or hydroxy;        -   R₂ is hydrogen;    -   or R₁ and R₂ taken together form a second bond between the        carbon atoms bearing R₁ and R₂;        -   R₃ is —COOH or —COOR₄;        -   R₄ is an alkyl with 1 to 6 carbon atoms;        -   A, B, and D are the substituents of their rings, each of            which may be different or the same, and are selected from            the group consisting of hydrogen, halogens, alkyl, hydroxy,            alkoxy, or other substituents            or a salt thereof. These compounds are useful in            pharmaceutical compositions, particularly as antihistamines,            antiallergy agents, and bronchodilators.

The piperidine derivative compound is prepared by a process which isinitiated by providing a substantially pure regioisomer of the followingformula:

The substantially pure regioisomer is converted to the piperidinederivative having a keto group with a piperidine compound of theformula:

A number of synthetic pathways for preparing the substantially pureregioisomer and for reacting it with the piperidine compound having aketo group are disclosed. The piperidine derivative having a keto groupcan be converted to the above piperidine derivative having a hydroxylgroup by reduction.

Although a wide variety of piperidine derivatives can be produced by theprocess of the present invention, it is particularly useful in forming ahydroxylated piperidine derivative of the formula:

Alternatively, the process of the present invention can be used toproduce a piperidine derivative with a keto group of the followingformula:

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to substantially pure piperidinederivative compounds of the formulae:

or

-   -   wherein        -   R₁ is hydrogen or hydroxy;        -   R₂ is hydrogen;    -   or R₁ and R₂ taken together form a second bond between the        carbon atoms bearing R₁ and R₂;        -   R₃ is —COOH or —COOR₄;        -   R₄ is an alkyl with 1 to 6 carbon atoms;        -   A, B, and D are the substituents of their rings, each of            which may be different or the same, and are selected from            the group consisting of hydrogen, halogens, alkyl, hydroxy,            alkoxy, or other substituents            or a salt thereof.

These substantially pure piperidine derivative compounds may be in theform of 4-diphenylmethylpiperidine derivatives represented by thefollowing formulae:

where A, B, D, R₃ are defined above. The substantially pure piperidinederivative compounds include 4-(hydroxydiphenylmethyl)piperidinederivatives according to the following formulae:

where A, B, D, R₃ are defined above. Another useful class of piperidinederivative compounds are 4-diphenylmethylenepiperidine derivatives inaccordance with the following formulae:

where A, B, D, R₃ are defined above. Examples of R₄ are straight orbranched alkyl groups, including methyl, ethyl, n-propyl, isopropyl,n-butyl, sec-butyl, tert-butyl, n-pentyl, neopentyl, and n-hexyl groups.

Illustrative examples of compounds of the present invention are asfollows:

-   4-[4-[4-(hydroxydiphenylmethyl-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic    acid;-   4-[4-[4-(diphenylmethyl)-1-piperidinyl]-hydroxybutyl]-α,α-dimethylbenzeneacetic    acid;-   4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic    acid;-   4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-3-hydroxybenzeneacetic    acid;-   4-[4-[4-hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-2-hydroxybenzeneacetic    acid;-   4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-3-hydroxybenzeneacetic    acid;-   5-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic    acid;-   ethyl    4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetic;-   n-pentyl    4-[4-[4-(diphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate;-   ethyl    4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate;-   methyl    4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate;-   ethyl    4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-(3-hydroxybenzene)acetate;-   n-propyl    4-[4-[4-(hydroxydiphenylmethyl-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-(2-hydroxybenzene)acetate;-   n-hexyl    4-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethyl-(3-hydroxybenzene)acetate;-   ethyl    5-[4-[4-(diphenylmethylene)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylbenzeneacetate;-   α,α-diphenyl-1-(4-(4-tert-butyl-2-hydroxy)phenyl)hydroxybutyl    piperidinemethanol;-   α,αdiphenyl-1-(4-(4-tert-butyl-3-hydroxy)phenyl)-4-hydroxybutyl-4-piperidinemethanol;-   α,α-diphenyl-1-(3-(4-tert-butyl-2-hydroxy)phenyl)-3-hydroxypropyl-4-piperidinemethanol;-   α,α-diphenyl-1-(5-(4-tert-butyl-2-acetyloxy)phenyl)-5-hydroxypentyl-4-piperidinemethanol;-   α,αdiphenyl-1-(4-(4-hydroxy-tert-butyl-2-hydroxy)-phenyl)-4-hydroxybutyl-4-piperidinemethanol;-   α,αdiphenyl-1-(4-(4-hydroxy-tert-butyl-3-hydroxy)-phenyl)-4-hydroxybutyl-4-piperidinemethanol;-   α,α-diphenyl-1-(3-(4-hydroxy-tert-butyl-2-hydroxy)-phenyl-3-hydroxybutyl-4-piperidinemethanol;-   α,α-diphenyl-1-(4-(4-hydroxy-tert-butyl)phenyl)-4-hydroxybutyl-4-piperidinemethanol;-   1-(4-tert-butyl-2-hydroxyphenyl)-4-(4-phenylmethylene)-1-(piperidinyl)butanol;-   1-(4-tert-butyl-3-hydroxyphenyl)-4-(4-diphenylmethylene)-1-(piperidinyl)butanol;-   1-(4-tert-butyl-3-hydroxyphenyl)-2-(4-diphenylmethylene)-1-(piperidinyl)butanol;-   1-(4-tert-butyl-2-butyryloxyphenyl)-6-(4-(diphenylmethyl)-1-piperidinyl)hexanol;-   1-(4-hydroxy-tert-butyl-2-hydroxyphenyl)-4-(4-(diphenylmethylene)-1-(piperidinyl)butanol;-   1-(4-hydroxy-tert-butyl-3-hydroxyphenyl)-4-(4-(diphenylmethylene)-1-(piperidinyl)butanol;-   1-(4-hydroxy-tert-butylphenyl)-4-(4-(diphenylmethylene)-1-(piperidinyl)butanol;    Particularly preferred are compounds of the formulae:

and

Optionally, both diphenyl groups from the piperidine compound may bealkyl (e.g., methyl) substituted at the position para to the methylene.

This invention also includes pharmaceutically acceptable salts in theform of inorganic or organic add or base addition salts of the abovecompounds. Suitable inorganic acids are, for example, hydrochloric,hydrobromic, sulfuric, and phosphoric acids. Suitable organic acidsinclude carboxylic adds, such as, acetic, propionic, glycolic, lactic,pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamicascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic,4-aminobenzoic, anthranillic, cinnamic, salicyclic, 4-aminosalicyclic,2-phenoxybenzoic, 2-acetoxybenzoic, and mandelic acid. Sulfonic acids,such as, methanesulfonic, ethanesulfonic, and β-hydroxyethane-sulfonicacid are also suitable acids. Non-toxic salts of the compounds of theabove-identified formulas formed with inorganic and organic basesinclude, for example, those alkali metals, such as, sodium, potassium,and lithium, alkaline earth metals, for example, calcium and magnesium,light metals of group IIIA, for example, aluminum, organic amines, suchas, primary, secondary, or tertiary amines, for example,cyclohexylamine, ethylamine, pyridine, methylaminoethanol, andpiperazine. These salts are prepared by conventional means, for example,by treating the piperidine derivative compounds of the formula:

or

where R₁, R₂, and R₃ are defined above, with an appropriate acid orbase.

The piperidine derivative compounds of the present invention can beutilized as the biologically active components in pharmaceuticalcompositions. The compounds of this invention are useful asantihistamines, antiallergy agents, and bronchodilators. They may beadministered alone or with suitable pharmaceutical carriers, and can bein solid or liquid form such as, tablets, capsules, powders, solutions,suspensions or emulsions.

The compounds of this invention can be administered orally,parenterally, for example, subcutaneously, intravenously,intramuscularly, intraperitoneally, by intranasal instillation or byapplication to mucous membranes, such as, that of the nose, throat andbronchial tubes. Such application to mucous membranes can be achievedwith an aerosol spray containing small particles of a compound of thisinvention in a spray or dry powder form.

The quantity of the compound of the present invention administered willvary depending on the patient and the mode of administration and can beany effective amount. The quantity of the compound administered may varyover a wide range to provide in a unit dosage an effective amount offrom about 0.01 to 20 mg/kg of body weight of the patient per day toachieve the desired effect. For example, the desired antihistamine,antiallergy, and bronchodilator effects can be obtained by consumptionof a unit dosage form such as a tablet containing 1 to 50 mg of thecompound of the present invention taken 1 to 4 times daily.

The solid unit dosage forms can be of the conventional type. This, thesolid form can be a capsule, such as an ordinary gelatin type containingthe compound of the present invention and a carrier, for example,lubricants and inert filers such as, lactose, sucrose, or cornstarch. Inanother embodiment, these compounds are tableted with conventionaltablet bases such as lactose, sucrose, or cornstarch in combination withbinders like acacia, cornstarch, or gelatin, disintegrating agents suchas, cornstarch, potato starch, or alginic acid, and a lubricant likestearic acid or magnesium stearate.

The compounds of this invention may also be administered in injectabledosages by solution or suspension of the compounds of the presentinvention in a physiologically acceptable diluent with a pharmaceuticalcarrier. Such carriers include sterile liquids such as water and oils,with or without the addition of a surfactant and other pharmaceuticallyacceptable adjuvants. Illustrative oils are those of petroleum, animal,vegetable, or synthetic origin, for example, peanut oil, soybean oil, ormineral oil. In general, water, saline, aqueous dextrose and relatedsugar solution, and glycols such as, propylene glycol or polyethyleneglycol, are preferred liquid carriers, particularly for injectablesolutions.

For use as aerosols the compounds of this invention in solution orsuspension may be packaged in a pressurized aerosol container togetherwith suitable propellants, for example, hydrocarbon propellants likepropane, butane, or isobutane with conventional adjuvants. The compoundsof the present invention also may be administered in a non-pressurizedform such as in a nebulizer or atomizer.

The compounds of the present invention can be used to treat warm bloodedanimals, birds, and mammals. Examples of such beings include humans,cats, dogs, horses, sheep, cows, pigs, lambs, rats, mice, and guineapigs.

The piperidine derivative compounds of the present invention areprepared by providing a substantially pure regioisomer of the followingformula;

and then converting the substantially pure regioisomer to the piperidinederivative compounds of the invention having a keto group with apiperidine compound of the formula:

The resulting piperidine derivative compounds with a keto group can beconverted by reduction to the above-described piperidine compounds witha hydroxyl group.

There are several techniques of providing these substantially pureregioisomers.

Process One for Producing Substantially Pure Regioisomer

In one embodiment of the present invention, the substantially pureregioisomer is formed by initially acylating a starting compound of theformula:

wherein

-   -   R₅ is —OR₆, —N(R₆)₂, and —SR₆, and    -   R₆ is an alkyl with 1 to 6 carbons,        with a compound of the formula:

wherein

-   -   X is a halogen,        under conditions effective to produce a first mixture of        regioisomers of the formula:

Such conditions include those conventionally utilized in aFriedel-Crafts acylation reaction catalyzed by, for example, AlCl₃. Thereaction is carried out in a solvent such as, carbon disulfide,tetrachloroethane, or nitrobenzene with carbon disulfide being thepreferred solvent. The reaction is carried out for a time period of ½ to12 hours, preferably 3 to 5 hours, at a temperature of 0 to 25 C.

The first mixture of regioisomers can be hydrolyzed under conditionseffective to form a second mixture of regioisomers of the formula:

Typically this reaction is carried out by base hydrolysis procedureswhich are well known in the art. For example, the first mixture ofregioisomers can be treated with an inorganic base, such as, sodiumhydroxide or potassium hydroxide, in an aqueous lower alcohol solvent.Suitable solvents include aqueous methanol, ethanol, isopropanol, orn-butanol solutions Hydrolysis is carried out at reflux temperatures ofthe solvent for ½ to 12 hours.

Following such hydrolyzation, the substantially pure regioisomer of theformula:

is recovered from the second mixture of regioisomers. Such recovery iscarried out by crystallizing the substantially pure regioisomer salt ofthe formula:

wherein

X⁺ is a Lewis Acid

Such crystallization is carried out by fractional crystallizationtechniques known in the art. Generally, such procedures involvedissolving the second mixture of regioisomers in a solvent containing asalt at temperatures of 20 C to the reflux temperature of the solvent.The resulting solution is then slowly cooled to temperatures of −20 to25 C.

Suitable solvents for fractional crystallization include: alcoholsolvents, like methanol, ethanol, isopropyl alcohol, and n-butanol;ketone solvents, such as acetone or methyl ethyl ketone;ester-containing solvents, like ethyl acetate or isopropyl acetate;ethereal solvents such as tetrahydrofuran; acetonitrile; anddimethylformamide. Ethyl acetate is preferred.

Suitable salts for fractional crystallization are those where X⁺ is analkali metal salt, like sodium and potassium salts, or, more preferably,ammonium salts of the form NR₇R₈R₉, where R₇, R₈, and R₉ is hydrogen ora straight or branched alkyl of 1 to 6 carbon atoms which may besubstituted at any position with a phenyl ring or a substituted phenylring. The ammonium salt can also be cinchonidine, quinine, quinidine,quinuclidine, brucine, thebaine, or cinchonine. Of these salt complexes,cinchonidine is preferred.

The substantially pure regioisomer salt is then isolated by filtrationand converted to the substantially pure regioisomer of the formula:

by procedures well Blown in the art. Typically, such conversion isaccomplished by treatment with acid.

Process Two for Producing Substantially Pure Regioisomer

In another embodiment of the process of the present invention, thesubstantially pure regioisomer is produced by acylating a startingcompound of the formula:

wherein

-   -   R₃ is COOH, —COOalkyl, —CON(alkyl)₂, —COSalkyl where the alkyl        moieties have 1 to 6 carbon atoms and are straight or branched        with a compound of the formula:

wherein

-   -   X₁ is a halogen, trialkyl tin, trialkyl borate, triflate, or        organometallic reagents of lithium or magnesium derived from        bromine or iodine, with any allyl groups having 1 to 4 carbon        atoms and being straight or branched under conditions effective        to produce the substantially pure regioisomer of the formula:

This acylation reaction is carried out in a suitable solvent in thepresence of an appropriate catalyst for about 1 to 120 hours and attemperatures of about 0 C to the reflux temperature of the solvent.Suitable solvents for acylation include: hydrocarbon solvents, such asbenzene, toluene, xylene, or cyclohexane; halogenated hydrocarbons, suchas chlorobenzene, dichloroethane, methylene chloride, chloroform, orcarbon tetrachloride; carbon disulfide; dimethylformamide; etherealsolvents, like tetrahydrofuran and diethylether; or dioxane.

A variety of catalysts may be utilized when A is hydrogen. Suitablecatalysts include palladium catalysts, like palladium chloride,palladium acetate, tetrakis(triphenylphosphine)palladium(0),dichlorobis(triphenylphosphine palladium(II), orbenzylchlorobis(triphenylphosphine)palladium(II); or nickel-phosphinecatalysts. Acylation may also be carried out in the presence of addedlithium chloride or triphenylphosphine. The latter acylation reaction isknown in the art as organometallic cross coupling reactions and areconducted by the general procedures of D. Milstein, et al., J. Org.Chem., 1979, 44, 1613; J. W. Labadie, et al., J. Org. Chem. 1983, 48,4634; C. Sahlberg, et al., Tetrahedron Letters, 1983, 24, 5137; D.Milstein, et al., J. Am. Chem. Soc., 1978, 100, 3636; and K. Tamao, etal., Tetrahedron, 1982, 38, 3347.

Process Three for Producing Substantially Pure Regioisomer

In another embodiment of the process of the present invention, thesubstantially pure regioisomer is produced by acylating a startingcompound of the formula:

wherein

R₅ is —OR₆, —N(R₆)₂, and —SR₆, and

R₆ is an alkyl with 1 to 6 carbon atoms

with a compound of the formula:

under conditions effective to produce a first mixture of regioisomers ofthe formula:

Typically, such acylation is carried out by a Friedel-Crafts reaction,as described above in Process One for Producing Substantially PureRegioisomers.

The substantially pure regioisomer salt is recovered by fractionalcrystallization, isolation, and converting, as described above withreference to Process One for Producing Substantially Pure Regioisomers.

Once the substantially pure regioisomer of the present invention isproduced by one of the above (or some other) process, there are a numberof procedures for using that compound to produce the piperidinederivatives of the present invention.

Process One of Converting the Substantially Pure Regioisomer to theSubstantially Pure Piperidine Derivative Having a Keto Group

According to one aspect of the present invention, the substantially pureregioisomer can be halogenated under conditions effective to form afirst intermediate compound of the formula:

wherein X is a halogen.

Suitable halogens include chlorine, bromine, and iodine. Suitableconditions for carrying out such halogenating include reacting thesubstantially pure regioisomer with a halogen nucleophile and a LewisAcid. The ring opening reaction is carried out in a suitable solvent,optionally in the presence of a catalytic amount of base for about 0.5to 24 hours and a temperature of about 40 degrees C. to the refluxtemperature of the solvent. Suitable halogen nucleophiles include sodiumiodide, sodium bromide, potassium iodide, potassium bromide, cesiumIodide, cesium bromide, trimethylsilyl iodide, manganese iodide, ceriumiodide, magnesium bromide, magnesium iodide, magnesium carbonate,calcium bromide, and calcium iodide. Suitable Lewis Acids includesilicon compounds such as trimethylsilyl chloride and trimethylsilyliodide; aluminum compounds such as aluminum chloride, trimethylaluminum, diethyl aluminum chloride, ethyl aluminum dichloride, anddiethyl aluminum cyanide; magnesium salts; and boron salts. Suitablesolvents for the ring opening reaction include hydrocarbon solvents,such as, benzene, toluene, xylene, or cyclohexane; ethereal solventssuch as ether, tetrahydrofuran, dioxane, or dimethoxyethane; orhalogenated hydrocarbons, such as, chlorobenzene, methylene chloride,carbon tetrachloride, chloroform, or dichloroethane.

After such halogenation, the first intermediate compound is reacted witha piperidine compound of the formula:

under conditions effective to form the piperidine derivative compoundhaving a keto group of the formula:

This alkylation reaction is carried out in a suitable solvent preferablyin the presence of a base and, optionally, in the presence of acatalytic amount of potassium iodide for about 4 to 120 hours at atemperature of about 7° C. to the reflux temperature of the solvent.Suitable solvents for the alkylation reaction include alcohol solvents,such as, methanol, ethanol isopropyl alcohol, or n-butanol; ketonesolvents, such as, methyl isobutyl ketone; hydrocarbon solvents, suchas, benzene, toluene, or xylene; halogenated hydrocarbons, such as,chlorobenzene or methylene chloride; or dimethylformamide. Suitablebases for the alkylation reaction include inorganic bases, for example,sodium bicarbonate, potassium carbonate, or potassium bicarbonate ororganic bases, such as a trialkylamine, for example, triethylamine orpyridine, or an excess of the piperidine compound can be used.

When R₃ is —COOalkyl, the alkylation reaction is followed by basehydrolysis to convert R₃ substituents that are —COOalkyl groups to —COOHgroups. Such base hydrolysis involves treatment of the substantiallypure piperidine derivative with an inorganic base, such as, sodiumhydroxide in an aqueous lower alcohol solvent, such as, aqueousmethanol, ethanol, isopropyl alcohol, or n-butanol at reflux-temperaturefor about ½ hour to 12 hours.

Piperidine compounds where each of R₁ and R₂ is hydrogen or wherein R₁is hydroxy and R₂ is hydrogen are commercially available or may beprepared according to procedures well known in the art (e.g. F. J.McCarty, C. H. Tilford, M. G. Van Campen, J. Am. Chem. Soc. 1961, 26,4084). Piperidine compounds wherein R₁ and R₂ form a second bond betweenthe carbon atoms bearing R₁ and R₂ may be prepared by dehydration of thecorresponding compound wherein R₁ is hydroxy by procedures generallyknown in the art.

Second Process for Converting Substantially Pure Regioisomer toSubstantially Pure Piperidine Derivative Having a Keto Group

In another embodiment of the present invention, the substantially pureregioisomer of the formula:

is reacted directly with a piperidine compound of the formula:

under conditions effective to form the piperidine derivative compoundhaving a keto group of the formula:

This alkylation reaction is carried out in a suitable solvent preferablyin the presence of a base and optionally in the presence of a Lewis Acidsuch as magnesium, cesium, or calcium salts or trimethylsilyl chlorideor in the presence of a catalytic amount of potassium iodide for about 4to 120 hours at a temperature of about 70 C to the reflux temperature ofthe solvent. Suitable solvents for the alkylation reaction includealcohol solvents, such as, methanol, ethanol, isopropyl alcohol, orn-butanol; ketone solvents, such as, methyl isobutyl ketone; hydrocarbonsolvents, such as, benzene, toluene, or xylene; and halogenatedhydrocarbons, such as, chlorobenzene or methylene chloride; ordimethylformamide. Suitable bases of the alkylation reaction includeinorganic bases, for example, sodium bicarbonate, potassium carbonate,or potassium bicarbonate or organic bases, such as, a trialkylamine, forexample, triethylamine or pyridine, or an excess of a compound of thepiperidine compound may be used.

Processes for Reduction of Keto Group in Substantially Pure PiperidineDerivative

As discussed above, the process of the present invention is useful inproducing substantially pure piperidine derivatives with either a ketogroup or a hydroxyl group. Derivatives with keto groups can be convertedto similar compounds with hydroxyl groups by reduction reactions whichare well known in the art.

Reduction can be carried out with sodium borohydride or potassiumborohydride in lower alcohol solvents, such as, methanol, ethanol,isopropyl alcohol, or n-butanol.

When lithium aluminum hydride or diborane are used as reducing agents,suitable solvents are ethers, for example, diethyl ether,tetrahydrofuran, or dioxane. These reduction reactions are carried outat temperatures ranging from about 0 C to the reflux temperature of thesolvent, and the reaction time varies from about 0.5 to 8 hours.

Catalytic reduction may also be employed using, for example, Raneynickel, palladium, platinum or rhodium catalysts in lower alcoholsolvents, such as, methanol, ethanol, isopropyl alcohol, or n-butanol oracetic add or their aqueous mixtures, or by the use of aluminumisopropoxide in isopropyl alcohol. Reduction using sodium borohydride isgenerally preferred over catalytic reduction when forming carboxylicadds or esters. When the starting material is an ester, lithium aluminumhydride is the preferred reducing agent, while diborane is preferredwhen starting with an acid.

When esters with hydroxyl groups have been formed, base hydrolysis canbe used to produce a carboxylic acid. Such procedures are well known andgenerally involve treatment with an inorganic base, such as, sodiumhydroxide or potassium hydroxide, in an aqueous lower alcoholic solvent,such as aqueous methanol, ethanol, isopropyl alcohol, or n-butanol. Basehydrolysis is carried out at about the solvent reflux temperature forabout ½ hour to 12 hours.

EXAMPLES Example 1 Preparation of Ethyl 3- and4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate

Aluminum chloride (44 g; 0.33 mol) was added slowly in portions to asolution of freshly distilled 4-chlorobutyryl chloride (17 mL; 0.15 mol)in 460 mL of carbon disulfide at −10 C under a nitrogen atmosphere. Themixture was stirred for 15 minutes, then the cooling bath was removedand the mixture was allowed to warm to ambient temperature. The mixturewas stirred then for 15 minutes more, then cooled again to −10 C and qsolution of ethyl α,α-dimethylphenyl acetate (26.6 g; 0.14 mol) in 70 mLof carbon disulfide was added dropwise. The mixture was maintained withstirring for 3 her, then stirred overnight at room temperature.

The reaction mixture was partitioned between H₂O and CHCl₃. The combinedorganic portions were washed with saturated aqueous NaHCO₃ solution,dried over MgSO₄, filtered and concentrated in vacuo. The residue wasdissolved in CH₂Cl₂ and filtered through a plug of SiO₂, eluting with10% EtOAc in hexane. Concentration of the product-containing fractionsafforded 39.4 g of ethyl 3- and4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate as a mixture ofaromatic regioisomers.

Example 2 Preparation of4-Cyclopropyl-oxo-methyl)-α,α-dimethylphenylacetic acid

To a solution of 39.4 g of ethyl 3- and4-(4-chloro-1-oxobutyl)-α,α-dimethylphenylacetate obtained in Example 1dissolved in 800 mL of CH₃OH and 200 mL of H₂O was added 40 g of NaOH.The resulting mixture was refluxed for one hour. The cooled mixture wasthen concentrated in vacuo to remove the CH₃OH. The concentrate wasdiluted with H₂O and washed with two portions of EtOAc. The aqueouslayer was acidified with concentrated HCl and extracted with twoportions of EtOAc. The extracts were dried over MgSO₄, filtered, andconcentrated in vacuo to afford 30.3 g of crude product.

The crude product was dissolved in 600 mL of EtOAc, 38 g of cinchonidinewas added, and the mixture was stirred overnight. The resulting solidswere filtered and washed with EtOAc and sucked dry under a rubber dam toafford 25 g of a tan solid.

The solids were partitioned between EtOAc and 2N HCl. The aqueous layerwas extracted with EtOAc. The combined organics were dried over MgSO₄filtered, and concentrated in vacuo to afford 10.6 g of an oil (33% fromethyl α,α-dimethyl-phenylacetate).

Example 3 Preparation of 4-(4-Iodo-1-oxobutyl)-α,α-dimethylphenylaceticacid

A solution of 10.5 g of4-(cyclopropyl-oxo-methyl)-α,α-dimethylphenylacetic acid, prepared inaccordance with Example 2, in 250 mL of CH₂Cl₂ was cooled in an ice-MeOHbath and 25 g of trimethylsilyliodide was then added rapidly viapipette. The mixture was stirred in the ice bath for one hour, warmed toambient temperature, and stirred for one hour. A solution of aqueoussodium bisulfite was then added and the mixture was stirred well. Thephases were partitioned and the aqueous layer was extracted with CH₂Cl₂.The combined organics were washed with saturated aqueous NaCl, driedover MgSO₄, filtered, and concentrated in vacuo to afford 12.6 g (77%)of 4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid.

Example 4 Preparation of Methyl4-(4-Iodo-1-oxobutyl)-α,α-dimethylphenylacetate

To a solution of 12.6 g of4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetic acid, prepared inaccordance with Example 3, in 100 mL of Et₇₀ cooled in an ice bath, wasadded 40 mL of ethereal CH₂N₂. The mixture was stirred at 0 C for fewminutes, then let stand for 2 hr. A few drops of AcOH were added todecompose excess CH₂N₂, then the mixture was filtered and stripped toafford 12.6 g (96%) of methyl4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetate.

Example 5 Preparation of Methyl4-[4-[4-Hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetate

A solution of 12.6 g of methyl4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetate, prepared in accordancewith Example 4, in 500 mL of toluene in a one liter three neck flaskwith mechanical stirring was added 8.8 g of4-(α,α-diphenyl)piperidinemethanol and 23 g of K₂CO₃ and the mixture wasrefluxed for 7 hr. The cooled reaction mixture was then filtered andconcentrated in vacuo. The residue was dissolved in Et₂O and treatedwith excess ethereal HCl. The mixture was then concentrated to a solid.The solid was treated with EtOAc and collected by filtration. Theproduct was then partitioned between EtOAc and 2N Na₂CO₃. The organicswere dried over MgSO₄, filtered, and concentrated in vacuo to afford13.5 g (79%) of methyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,αdimethylphenylacetate.

Example 6 Preparation of Methyl4-[4-[4-Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate

A solution of 135 g of methyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetate,prepared in accordance with Example 5, in 250 mL of CH₃OH was cooled inan ice-CH₃OH bath and 1.8 g of NaBH₄ was added in portions. After 1 hr,the mixture was concentrated to a solid. The residue was partitionedbetween EtOAc and saturated aqueous NaHCO₃. The aqueous portion wasextracted with EtOAc. The combined organics were washed with saturatedaqueous NaCl, dried over MgSO₄ filtered, and concentrated in vacuo toafford 9.5 g (70%) of methyl4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetateas a foam.

Example 7 Preparation of4-[4-[4-Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylaceticAcid

To a solution of 95 g ofmethyl-4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate,prepared in accordance with Example 6, in 300 mL of CH₃OH and 150 mL ofH₂O was added 10 g of NaOH. The mixture was refluxed for 1 hr, thencooled. The CH₃OH was removed in vacuo. The concentrate was diluted withH₂O and CHCl₃ and the pH adjusted to approximately 5.5 to 6.0. Thephases were separated and the aqueous phase was extracted with CHCl₃.The combined organics were dried over MgSO₄, filtered, and stripped toafford 9.0 g of crude product.

The crude product was dissolved in CH₂Cl₂ and chromatographed on DavisilGrade 633 SiO₂ eluting with a gradient of CHCl₃, to 10% CH₃OH in CHCl₃,to 25% CH₃OH in CHCl₃. The product containing fractions wereconcentrated to afford 5.2 g of white crystals. An analytical sample wasprepared by treatment of the product with EtOAc, mp 199-203 C. Calc. forC₃₂H₃₉NO₄: C, 76.62; H, 7.84; N, 2.79. Found: C, 76.24; H, 7.76; N,2.75.

Example 8 Preparation of Methyl4-[4-[4-(Bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetate

To a solution of 6.4 g (0.017 mol) of methyl4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylacetate, prepared in accordancewith Example 4, in 500 mL of toluene in a one liter round bottom flaskequipped with a mechanical stirrer was added 5.1 g (0.017 mol) of4-α,αbis(4-methylphenyl)-piperidinemethanol, followed by 11.8 g(0.086-mol) of solid potassium carbonate. The solution was heated toreflux for 24 hr. After cooling, the mixture was filtered and thetoluene was removed in vacuo. The residue was partitioned between ethylacetate and 2 N sodium bicarbonate solution. The aqueous layer wasextracted twice with ethyl acetate, the combined organic layers weredried with sodium sulfate and the ethyl acetate was removed in vacuo toprovide 6.8 g (73%) of methyl4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetateas a viscous, dark colored oil.

Example 9 Preparation of Methyl4-[4-[4-Bis(4-Methylphenyl)hydroxymethyl)-1-piperidinyl]-hydroxybutyl]-α,α-dimethylphenylacetate

To a −10 C solution of 6.8 g (0.013 mol) of methyl4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylacetate,prepared in accordance with Example 8, in 150 mL of methanol in a 500 mLround bottom flask equipped with a mechanical stirrer was slowly added0.86 g (0.023 mol) of sodium borohydride, and the reaction was stirredfor 2 hr. The methanol was removed in vacuo and the residue waspartitioned between ethyl acetate and aqueous sodium bicarbonatesolution. The aqueous layer was extracted with ethyl acetate, thecombined organic layers were dried with sodium sulfate, and the ethylacetate was removed in vacuo to provide 6.9 g of a dark colored foam.The resultant material was purified by column chromatography (Davisilgrade 633 silica gel, packed in methylene chloride, material applied inchloroform, and eluted with a gradient of 2% methanol to methylenechloride to 5% methanol to methylene chloride) to afford 5.3 g (77%) ofmethyl4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate.

Example 10 Preparation of4-[4-[4-(Bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylaceticAcid

To 350 mL of methanol in a 1 L round bottom flask equipped with amechanical stirrer was added 5.3 g (9.8 mmol) of methyl4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylacetate,prepared in accordance with Example 9, 5.1 g (0.13 mmol) of solid sodiumhydroxide, and 100 mL of water. The mixture was heated to reflux for 3hr. After cooling, the methanol was removed in vacuo, and 6 Nhydrochloric acid was added dropwise until the solution was no longerbasic (pH=7). The solution was extracted three times with ethyl acetate.The organic layers were combined and a white crystalline solidprecipitated out of solution. The solid was washed with ether to provide1.8 g (34%) of4-[4-[4-(bis(4-methylphenyl)hydroxymethyl)-1-piperidinyl]1-hydroxybutyl]-α,α-dimethylphenylaceticacid, as the dihydrate, mp 208-215 C. Analysis. Calcd. forC₃₄H₄₃NO₄-2(H₂O): C, 72.18; H, 8.37; N, 2.47. Found: C, 72.02; H, 8.36;N, 2.41.

Example 11 Preparation of4-(1-Hydroxy-4-iodobutyl)-α,α-dimethylphenylacetic acid

To a solution of 50 mg of 4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylaceticacid, prepared in accordance with Example 3, in 3 mL of methanol wasadded 50 mg of NaBH₄. The mixture was stirred for 30 minutes, acidifiedwith 2N HCl, and the methanol removed in vacuo. The concentrate wasextracted with EtOAc. The organics were dried over Na₂SO₄, filtered, andconcentrated to afford 40 mg of4-(1-hydroxy-4-iodobutyl)-α,α-dimethylphenylacetic acid.

Example 12 Preparation of4-[4-[4-(Hydroxydiphenylmethyl)-1)-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylaceticacid

A mixture of 800 mg of 4-(4-iodo-1-oxobutyl)-α,α-dimethylphenylaceticacid, prepared in accordance with Example 3, 800 mg of4-(α,α-diphenyl)piperidinemethanol, and 2.4 g of K₂CO₃ in 25 mL oftoluene was stirred for 48 hours at room temperature. The mixture wasconcentrated in vacuo. The residue was treated with EtOAc, filtered, andconcentrated to afford4-[4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylaceticacid.

Example 13 Preparation of4-[4-[4-Hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylaceticAcid

A mixture of4-[4-[(hydroxydiphenylmethyl)-4-piperidinyl]-1-oxobutyl]-α,α-dimethylphenylaceticacid, prepared in accordance with Example 12, and 300 mg of NaBH₄ in 25mL of CH₃OH was stirred overnight at room temperature. The mixture wasthen concentrated in vacuo. The residue was partitioned between EtOAcand H₂O. The aqueous portion was treated with concentrated HCl until pH6, then extracted with EtOAc. The organics were concentrated in vacuo.The residue was dissolved in EtOAc, filtered, and concentrated in vacuoto an oil. The oil was dissolved in CH₃OH and concentrated to a solid.The solid was slurried with EtOAc, filtered, and rinsed with EtOAc toafford4-[4-[4-hydroxydiphenylmethyl)-1-piperidinyl]-1-hydroxybutyl]-α,α-dimethylphenylaceticacid.

Although the invention has been described in detail for the purpose ofillustration, it is understood that such detail is solely for thatpurpose, and variations can be made therein by those skilled in the artwithout departing from the spirit and scope of the invention which isdefined by the following claims.

1-31. (canceled)
 32. A process of preparing a compound of formula I:

R₁ is hydrogen or hydroxy; R₂ is hydrogen; or R₁ and R₂ taken togetherform a second bond between the carbon atoms bearing R₁ and R₂; R₃ is—COOH or —COOR₄; R₄ is an alkyl of 1 to 6 carbon atoms; said processcomprising: acylating a starting compound of formula II:

wherein R₅ is —SR₆ and R₆ is an alkyl of 1 to 6 carbon atoms with acompound of formula III:

under conditions effective to produce a first mixture of regioisomers offormula IV:

hydrolyzing the first mixture of regioisomers of formula IV underconditions effective to form a second mixture of regioisomers of formulaV:

recovering from the second mixture of regioisomers of formula V theregioisomer of formula VI:

converting the regioisomer of formula VI to the compound of formula Iwith a piperidine compound of formula VII:


33. A process according to claim 32, wherein said recovering comprises:crystallizing a regioisomer salt of formula VIII:

wherein X⁺ is a Lewis Acid from the second mixture of regioisomers offormula V; isolating the regioisomer salt of formula VIII; andconverting the regioisomer salt of formula VIII to a regioisomer offormula VI:


34. A process according to claim 33, wherein X⁺ is an alkali metal saltor an ammonium salt of the form NR₇R₈R₉ wherein R₇, R₈, and R₉ ishydrogen or a straight or branched alkyl of 1 to 6 carbon atoms, or analkyl substituted at any position with a phenyl ring or a substitutedphenyl ring.
 35. A process according to claim 34, wherein X⁺ iscinchonidine.
 36. A process according to claim 32, wherein saidacylating is carried out by a Friedel-Crafts reaction using AlCl₃.
 37. Aprocess according to claim 32, further comprising: reducing the compoundof formula I under conditions effective to form a compound of formulaIX:


38. A process according to claim 37, wherein the compound of formula IXis:


39. A process according to claim 32, wherein said converting comprises:hydrohalogenating a regioisomer of formula X:

under conditions effective to form a first intermediate compound offormula XI:

wherein X is a halogen and reacting the first intermediate compound offormula XI with the piperidine compound of formula VII:

under conditions effective to form the compound of formula I:


40. A process according to claim 32, wherein said converting comprises:reacting a regioisomer of formula X:

with the piperidine compound of formula VII:

under conditions effective to form the compound of formula I:


41. A process according to claim 32, wherein the compound of formula Iis: